P21 INHIBITOR UC2288 (C15-1305-085)

General description

A cell-permeable compound that selectively downregulates the expression of p21 (~10 µM), independent of p53.expression, at either transcription or post-transcriptional level.

A cell-permeable phenylcyclohexyl-urea compound that downregulates cellular p21/Cip1/CKI/Waf1 protein level (by >95% in HCT116 cells after 24 h UC2288 treatment at 2.5 µM), presumably by means of a yet undetermined transcriptional or post-transcriptional regulation without affecting p21 cellular half-life or inhibiting the kinase activities of C-raf, B-raf^V600E, or VEGFR2 (IC₅₀ >10 µM). Dual telomerase and p21, but not p16 or p27 (gene = CDKN1A, CDKN2A, CDKN1B, respectively), knockdown/inhibition is demonstrated to effectively kill cancer cells both in vitro (% viability inhibition/% Annexin V+ cells induction = 20%/2% or 77%/55%, respectively, following telomerase inhibition by Imetelstat with or without 2.5 µM UC2288 for 24 h in HCT116 colon cancer cultures) and in mice in vivo (% tumor expansion suppression by UC2288 alone/Imetelstat alone/combined treatment = 13%/42%/90%/HCT116 and 4%/23%/92%/ACHN; 30 mg Imetelstat/kg via i.p. and/or 15 mg UC2288/kg via p.o. 3X/wk for 3 wk) by inducing p53- and E2F1-dependent PUMA expression, while p21 overexpression, p53 inactivation by mutation, shRNA-mediated E2F1 or PUMA downregulation abolishes such synergized cell killing. Likewise, reactivating mutant p53 activitiy by CP-31398 (Cat. No. 506166) treatment is reported to resensitize DLD1 (p53 S241F) and A375.S2 (p53 R273H & P309S) to p21 shRNA- & Imetelstat-induced apoptotic cell death and tumor growth inhibition.

A cell-permeable, orally available, phenylcyclohexyl-urea based compound that selectively downregulates the expression of p21 (~10 µM), independent of p53 expression, at either transcription or post-transcriptional level. However, it does not affect the stability of p21. Also, it has no significant effect on the activities of Raf kinases, VEGFR2 kinase, or the phosphorylation state of ERK. Effectively blocks the growth of multiple cancer cell lines (GI₅₀ ~ 10 µM against NCI60 cell lines). Its greater inhibitory effect on cytosolic p21 is indicative of its ability to induce apoptotic cell death in 786-O cells. Synergistically suppresses the growth of HCT116 and ACHN cells in athymic nude mice when combined with imetelstat, a telomerase inhibitor (15 mg/kg of UC2288, p.o., & 30 mg/kg of imetelstat, i.p., 3 times per week).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

Biochem/physiol Actions

Cell permeable: yes

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Use only fresh DMSO for reconstitution.

Other Notes

Gupta, R., et al. 2014. Proc. Natl. Acad. Sci. USA111, E3062.
Wettersten, H.I., et al. 2013. Cancer Biol. Ther.14, 278.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Molecular Weight: 481.82. Empirical Formula: C₂₀H₁₈ClF₆N₃O₂. Assay: ≥. 98% (HPLC). Quality Level: 100. form: solid. manufacturer/tradename: Calbiochem^®. . storage condition: OK to freeze, protect from light. color: white. solubility: DMSO: 50 . mg/mL. storage temp.: 2-8°C. SMILES string: O: C(N[C@@H]1CC[C@@H](OC2: CC: C(C: N2)C(F)(F)F)CC1)NC3: CC(C(F)(F)F): C(Cl)C: C3. Storage Class Code: 11 - Combustible Solids. WGK: WGK 3. Flash Point(F): Not applicable. Flash Point(C): Not applicable.